Selective Loss of Leptin Receptors in the Ventromedial Hypothalamic Nucleus Results in Increased Adiposity and a Metabolic Syndrome

Bingham, Nathan C.; Anderson, Kimberly K.; Reuter, Anne L.; Stallings, Nancy R.; Parker, Keith L.

doi:10.1210/en.2007-1200

Cited by 193 publications

(183 citation statements)

References 69 publications

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“…A large subset of VMN neurons also express the long form of the leptin receptor (LepRb), and a majority of these neurons also express SF1 (21,22). To determine whether activation of LepRb-expressing neurons in the VMN (VMN LepRb ) also causes hyperglycemia, we microinjected the Cre-dependent channelrhodopsin virus into the VMN of leptin receptor-IRES-Cre (Lepr-Cre + ) mice ( Fig.…”

Section: Vmn Sf1 Neurons Are Required For Intact Responses To Insulinmentioning

confidence: 99%

Functional identification of a neurocircuit regulating blood glucose

Meek

Nelson

Matsen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

159

187

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Previous studies implicate the hypothalamic ventromedial nucleus (VMN) in glycemic control. Here, we report that selective inhibition of the subset of VMN neurons that express the transcription factor steroidogenic-factor 1 (VMN SF1 neurons) blocks recovery from insulin-induced hypoglycemia whereas, conversely, activation of VMN SF1 neurons causes diabetes-range hyperglycemia. Moreover, this hyperglycemic response is reproduced by selective activation of VMN SF1 fibers projecting to the anterior bed nucleus of the stria terminalis (aBNST), but not to other brain areas innervated by VMN SF1 neurons. We also report that neurons in the lateral parabrachial nucleus (LPBN), a brain area that is also implicated in the response to hypoglycemia, make synaptic connections with the specific subset of glucoregulatory VMN SF1 neurons that project to the aBNST. These results collectively establish a physiological role in glucose homeostasis for VMN SF1 neurons and suggest that these neurons are part of an ascending glucoregulatory LPBN→VMN SF1 →aBNST neurocircuit.glucoregulatory circuit | counter regulation | ventromedial nucleus | bed nucleus of the stria terminalis | hyperglycemia B ecause the brain relies exclusively on glucose as a fuel source, brain function is rapidly compromised when circulating glucose levels drop below the normal range. Consequently, hypoglycemia elicits a robust, integrated, and redundant set of counterregulatory responses (CRRs) that ensure the rapid and efficient recovery of plasma glucose concentrations into the normal range (1). Components of the CRR include increased secretion of the hormones glucagon, epinephrine, and glucocorticoids, inhibition of glucoseinduced insulin secretion, increased sympathetic nervous system (SNS) outflow to the liver, and increased food intake (1-3). Owing to this redundancy, recovery from hypoglycemia is difficult to block in normal humans and animal models, even when adrenal or glucagon responses are prevented. Only when multiple responses are blocked is the ability to recover from hypoglycemia significantly compromised (4). This arrangement is perhaps unsurprising, given the threat to survival posed by hypoglycemia.Although glucose sensing can occur at peripheral (e.g., neurons innervating the hepatic portal vein) as well as central sites (3, 5), the brain is the organ responsible both for transducing this information into effective glucose counterregulation and for terminating this response once euglycemia is restored. Of the many brain areas that have been investigated, the hypothalamic ventromedial nucleus (VMN) has emerged as potentially being both necessary and sufficient to elicit this powerful response. This assertion is based on evidence that, whereas electrical stimulation of the VMN activates the CRR and thereby raises circulating glucose levels (6), glucose infusion directly into the VMN can suppress the CRR during hypoglycemia (7) and thereby impair recovery of normal blood glucose levels (8). Moreover, two recent papers identified a circuit comprise...

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Section: Vmn Sf1 Neurons Are Required For Intact Responses To Insulinmentioning

confidence: 99%

Functional identification of a neurocircuit regulating blood glucose

Meek

Nelson

Matsen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

159

187

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“…In support of this, neurons in the VMN express the leptin receptor [43] and are activated by leptin [44], injection of leptin into this brain area increases glucose uptake in peripheral tissues [45,46] and deletion of leptin receptors from neurons in the VMN causes mild obesity and an insulinresistant phenotype in mice [47,48]. In addition, this brain area is also involved in the control of glucagon secretion [49].…”

Section: Neurocircuitry Controlling Leptin's Glucose-lowering Effectsmentioning

confidence: 99%

The role of leptin in diabetes: metabolic effects

2016

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While it is well established that the adiposity hormone leptin plays a key role in the regulation of energy homeostasis, growing evidence suggests that leptin is also critical for glycaemic control. In this review we examine the role of the brain in the glucose-lowering actions of leptin and the potential mediators responsible for driving hyperglycaemia in states of uncontrolled insulin-deficient diabetes (uDM). These considerations highlight the possibility of targeting leptin-sensitive pathways as a therapeutic option for the treatment of diabetes. This review summa-

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“…6,7 Whole-body deletion of SF1 induces obesity but not hyperglycemia, whereas selective depletion of LepRb from SF1 neurons leads to weight gain, hyperinsulinemia and glucose intolerance. 8,9 VMH neurons express glucokinase, an important component of the glucose-sensing machinery, and the VMH acts as a major sensor of brain glucose levels. 10 Leptin treatment of the VMH promotes increased glucose uptake in peripheral tissues, though it is not clear whether this effect is mediated by direct connections with the sympathetic nervous system or through modulation of other hypothalamic neurons that project to the periphery.…”

Section: Leprb Neuron-containing Loci That Modulate Energy Homeostasismentioning

confidence: 99%

Location, location, location: the CNS sites of leptin action dictate its regulation of homeostatic and hedonic pathways

Leinninger

2009

Int J Obes

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The increasing incidence of obesity and obesity-linked disease presents a serious global health threat. To develop truly effective therapies to modulate food intake and promote weight loss, we must understand the physiological regulators that underlie these processes. One crucial mediator of food intake and energy homeostasis is the adipose-derived hormone, leptin, which acts through neurons expressing the long form of the leptin receptor (LepRb). Although most investigation of leptin action has centered on the large population of LepRb neurons in the arcuate nucleus (ARC), this nucleus does not mediate all aspects of leptin action. Indeed, several hypothalamic and extrahypothalamic loci contain substantial numbers of LepRb neurons, each of which presumably mediates distinct aspects of leptin action, and the collective output of these various LepRb populations produces the totality of leptin function. This review will examine known central nervous system loci that contain LepRb neurons and the potential roles for discrete populations of LepRb neurons in the control of homeostatic and hedonic pathways by leptin. Understanding the unique neuroanatomical and functional roles for each locus of leptin action will be important to identify how specific aspects of food intake contribute to obesity. International Journal of Obesity (2009) 33, S14-S17; doi:10.1038/ijo.2009.66Keywords: leptin; hypothalamus; energy balance; dopamine Leptin signaling is crucial for normal energy homeostasisThe incidence of obesity is increasing rapidly, predisposing millions of individuals to obesity-linked diseases such as type 2 diabetes that result in reduced life expectancy. In addition to the considerable personal toll exacted by obesity and its complications, the ongoing treatment of these conditions throughout a patient's life poses a staggering health care cost. These costs will only become more apparent with the dramatic ongoing rise in juvenile obesity that precipitates earlier onset of complications. Clearly, therapies to prevent weight gain and facilitate weight loss are needed, but our limited understanding of the systems that govern energy homeostasis has hindered the development of truly effective treatments.The discovery of leptin represents an important step in our understanding of how the body regulates food intake and energy homeostasis. Lack of leptin in rodents and humans results in obesity, diminished metabolic rate, hyperphagia and attenuated reproductive function. 1 Loss of the long form of the leptin receptor (LepRb) produces the same phenotype, showing the importance of leptin/ LepRb for normal physiology. 2 Although leptin is produced by adipocytes in approximate proportion to fat stores (that is, the more the adipose content, the more the leptin produced) and released into the circulation, LepRb is expressed, and leptin acts, primarily in the central nervous system on subsets of (primarily hypothalamic) neurons that control processes linked to the intake and expenditure of energy. 3 In aggregate, these clusters of...

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Selective Loss of Leptin Receptors in the Ventromedial Hypothalamic Nucleus Results in Increased Adiposity and a Metabolic Syndrome

Cited by 193 publications

References 69 publications

Functional identification of a neurocircuit regulating blood glucose

Functional identification of a neurocircuit regulating blood glucose

The role of leptin in diabetes: metabolic effects

Location, location, location: the CNS sites of leptin action dictate its regulation of homeostatic and hedonic pathways

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